AB0147 ANTI-FIBROTIC EFFECTS OF MT-5562, A NOVEL POTENT SELECTIVE AUTOTAXIN INHIBITOR, IN PRECLINICAL STUDIES: CLUES TO TREAT SKIN AND LUNG FIBROSIS IN SYSTEMIC SCLEROSIS
Authors: H. Matsuura, M. Kondo, R. Ohno, A. Ishii, M. Piruzyan, K. Funayama, Y. Ono, A. Iwamura, T. Endou, T. Akashi, T. Tomari, N. Uchiyama, G. Kania, P. Blyszczuk, O. Distler
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Autotaxin (ATX) is the lysophosphatidic acid (LPA)-producing enzyme. Targeted small-molecule therapies to ATX have been shown to be potentially effective in systemic sclerosis (SSc) treatment, but the clinical benefit and safety of selective inhibition remains unclear. <h3>Objectives</h3> To explore the potential of MT-5562, a novel oral selective inhibitor of ATX, as a therapeutic agent for SSc by evaluating its efficacy and toxicity in preclinical models. <h3>Methods</h3> MT-5562 and a free form of MT-5562 (MT-5562F) were evaluated, and other ATX inhibitors (ziritaxestat and cudetaxestat) were used as comparators in the present study. In vitro ATX activity was measured by choline assay using fluorescent substrate Amplex UltraRed. The effects of MT-5562F on IL-6 and connective tissue growth factor (CTGF) production in TGF-beta stimulated dermal fibroblasts from healthy donors and lung fibroblasts from idiopathic pulmonary fibrosis patients were evaluated in vitro. Cell toxicity was evaluated in human pulmonary alveolar epithelial cells (HPAEpiC), human lung fibroblasts from idiopathic pulmonary fibrosis patients (DHLF-IPF) and lung microvascular endothelial cells (HMVEC-L) by live cell counting. The plasma concentration of MT-5562F and LPA production were evaluated in C57BL/6 mice. The effects of MT-5562F on skin and lung fibrosis were evaluated in murine SSc models induced by bleomycin (BLM). <h3>Results</h3> MT-5562F, ziritaxestat, and cudetaxestat inhibited the enzyme activity of human ATX with IC50s of 0.45, 49.3, and 2.77 nmol/L, respectively. MT-5562F and ziritaxestat inhibited the enzyme activity of mouse ATX with IC50s of 0.15 and 10.9 nmol/L, respectively. MT-5562F concentration-dependently inhibited TGF-beta-induced IL-6 and CTGF production in human dermal fibroblasts from healthy donors and lung fibroblasts from IPF patients. MT-5562 showed minimal effects on cell viability using lung structural cells such as alveolar epithelial cells (HPAEpiC), pulmonary fibroblasts (DHLF-IPF) and endothelial cells (HMVEC-L) even at the maximum dissolved concentration (60 µmol/L). On the other hand, ziritaxestat showed more cytotoxic effects than MT-5562 on cell viability in vitro. MT-5562 didn't show any specific off-target inhibition on receptor binding and kinase profiling assays. In vivo, MT-5562F and ziritaxestat (10, 30 mg/kg) dose-dependently reduced plasma LPA concentration in mice according to the plasma drug exposure and mouse ATX inhibitory activity, and MT-5562F showed more sustained effects compared with ziritaxestat. Therapeutic treatment with MT-5562F (30, 60 mg/kg, once daily) significantly suppressed skin thickening and the numbers of myofibroblasts in pre-established subcutaneous BLM-induced skin fibrosis model. Therapeutic treatment with MT-5562F (30, 60 mg/kg, twice daily) and ziritaxestat (30 mg/kg, twice daily) showed significant reduction of the average Ashcroft score and collagen severity score in the BLM-induced lung fibrosis model together with the reduction of the biomarker LPA. All doses of MT-5562F significantly reduced the expression of inflammatory and fibrotic mediators such as C-reactive protein, IL-6R-alpha, epidermal growth factor receptor (EGFR) and periostin in bronchoalveolar lavage fluid. <h3>Conclusion</h3> Our results suggest that MT-5562 is a selective and potent ATX inhibitor. It is expected to be a safer compound comparing other ATX inhibitors under development, and it may offer a good option to treat lung and skin fibrosis in SSc. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Hiroshi Matsuura Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Masahiro Kondo Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Ryoko Ohno Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Akina Ishii Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Mariam Piruzyan Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Kaori Funayama Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Yuuichi Ono Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Atsushi Iwamura Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Tadashi Endou Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Tomoya Akashi Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Taizo Tomari Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Noriko Uchiyama Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Employee of: Mitsubishi Tanabe Pharma Corporation, Gabriela Kania: None declared, Przemyslaw Blyszczuk: None declared, Oliver Distler Speakers bureau: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant, Sanofi and Topadur., Consultant of: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant, Sanofi and Topadur., Grant/research support from: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant, Sanofi and Topadur.